This invention relates to antigen and antibody vaccine compositions related to enterically transmitted nonA/nonB hepatitis viral agent, also referred to herein as hepatitis E virus (HEV), and to vaccine methods.
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Enterically transmitted non-A/non-B hepatitis viral agent (ET-NANB, also referred to herein as hepatitis E virus or HEV) is the reported cause of hepatitis in several epidemics and sporadic cases in Asia, Africa, Europe, Mexico, and the Indian subcontinent. Infection is caused usually by water contaminated with feces, although the virus may also spread by close physical contact. The virus does not seem to cause chronic infection.
The viral etiology in HEV has been demonstrated by infection of volunteers with pooled fecal isolates; immune electron microscopy (IEM) studies have shown virus particles with 27-34 nm diameters in stools from infected individuals. The virus particles reacted with antibodies in serum from infected individuals from geographically distinct regions, suggesting that a single viral agent or class is responsible for the majority of HEV hepatitis seen worldwide. No antibody reaction was seen in serum from individuals infected with parenterally transmitted NANB virus (also known as hepatitis C virus or HCV), indicating a different specificity between the two NANB types.
In addition to serological differences, the two types of NANB infection show distinct clinical differences. HEV is characteristically an acute infection, often associated with fever and arthralgia, and with portal inflammation and associated bile stasis in liver biopsy specimens (Arankalle). Symptoms are usually resolved within six weeks. HCV, by contrast, produces a chronic infection in about 50% of the cases. Fever and arthralgia are rarely seen, and inflammation has a predominantly parenchymal distribution (Khuroo, 1980).
The course of HEV is generally uneventful in healthy individuals, and the vast majority of those infected recover without the chronic sequelae seen with HCV. One peculiar epidemiologic feature of this disease, however, is the markedly high mortality observed in pregnant women; this is reported in numerous studies to be on the order of 10-20%. This finding has been seen in a number of epidemiologic studies but at present remains unexplained. Whether this reflects viral pathogenicity, the lethal consequence of the interaction of virus and immune suppressed (pregnant) host, or a reflection of the debilitated prenatal health of a susceptible malnourished population remains to be clarified.
The two viral agents can also be distinguished on the basis of primate host susceptibility. HEV, but not HCV, can be transmitted to cynomolgus monkeys. HCV is more readily transmitted to chimpanzees than is HEV (Bradley, 1987).
In the earlier-filed parent applications, HEV clones, and the sequence of the entire HEV genome sequence were disclosed. From HEV clones, recombinant peptides derived from HEV genomic coding region were produced.
In one aspect, the invention includes a peptide vaccine composition for immunizing an individual against hepatitis E virus (HEV). The composition includes a pharmacologically acceptable carrier, and a peptide containing the C-terminal 42 amino acids of the putative capsid protein encoded by the second open reading frame of the HEV genome. The peptide preferably includes the amino acid sequence identified by one of the following sequences:
(i) Sequence ID No. 13
(ii) Sequence ID No. 14,
(iii) internally consistent variations between Sequence ID Nos.13 and 14,
(iv) Sequence ID No. 15
(v) Sequence ID No. 16,
(vi) internally consistent variations between Sequence ID Nos.15 and 16,
(vii) Sequence ID No. 17
(viii) Sequence ID No. 18,
(ix) internally consistent variations between Sequence ID Nos.17 and 18,
(x) Sequence ID No. 19
(xi) Sequence ID No. 20, and
(xii) Internally consistent variations between Sequence ID Nos.19 and 20, and
(xiii) Sequence ID No. 21
(xiv) Sequence ID No. 22, and
(xv) Internally consistent variations between Sequence ID Nos.21 and 22.
In a related aspect, the invention includes a method of inhibiting infection of an individual by HEV, by administering to the subject, by parenteral injection, such as intramuscular or intravenous injection, the above peptide vaccine composition.
In another aspect, the invention includes an antibody vaccine composition effective in neutralizing hepatitis E virus (HEV) infection, as evidenced by the ability of the composition to block HEV infection of primary human hepatocyte cells in culture.
The antibody composition preferably contains an antibody which is immunoreactive with a peptide containing one of the above (i)-(xv) sequences, and preferably with a peptide corresponding to sequences (i)-(iii), (iv-vi) and (vii-xv). In a related aspect, the invention includes a method for preventing or treating HEV infection in an individual, by administering to the subject, by parenteral injection, the above antibody composition.